I2/CHP mediated [1 + 1 + 1 + 1] cyclization of aromatic isocyanides with amines to construct 1,3-diazetidine-2,4-diimine derivatives

Article abstract of DOI:10.1039/c7ob02255g

An I₂/CHP (cumene hydroperoxide) mediated [1 + 1 + 1 + 1] cyclization of aromatic isocyanides with readily accessible amines via the formation 4 new C-N bonds has been developed to construct unsymmetric 1,3-diazetidine-2,4-diimine derivatives u

Full text of DOI:10.1039/c7ob02255g

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I2/CHP
Mediated
[1+1+1+1]
Cyclization
of
Aromaticisocyanide with Amine to Construct 1,3-
Diazetidine-2,4-diimine Derivatives†
Cite this: DOI: 10.1039/x0xx00000x
Hai-Feng Liu,a,b Tong-Hao Zhu,a Pei Xu,a Shun-Yi Wang,*a and Shun-Jun Ji*a
Received 00th January 2015,
Accepted 00th January 2015
DOI: 10.1039/x0xx00000x
www.rsc.org/
An I2/CHP (cumene hydroperoxide) mediated [1+1+1+1] reported the transition-metal catalyzed cross coupling reaction of
cyclization of aromatic isocyanide with readily accessible isocyanide with amine to furnish carbodiimides, respectively.
amine via 4 new C-N bonds formation has been developed
More recently, we have described an iodine-mediated reaction of
to construct unsymmetric 1,3-diazetidine-2,4-diimine isocyanide with amine to form carbodiimides.[11] As continuation of
derivatives under mild conditions.
our works on the reaction of isocyanide with amine,[12] herein, we
report an I2/CHP mediated [1+1+1+1] cyclization of aromatic
Isocyanides are important building blocks to construct versatile isocyanide with readily accessible amines via 4 new C-N bonds
molecules and widely applied in organic synthesis.[1] During the past formation to construct various unsymmetric 1,3-diazetidine-2,4-
decade, metal mediated or catalyzed reactions of isocyanides have diimine derivatives in moderate to excellent yields (Scheme 1).
attracted great attentions and well developed.[2,3] Despite these
progress, the development of novel, convergent, metal-free and
practical strategies for isocyanides insertion reactions is considerable
and still in urgent.
In 1940, Zetzsche and Fredrieh isolated the first symmetric 1,3-
diazetidine-2,4-diimine derivative in very low yield from the
distillation residue of dibenzylcarbodiimide.[4] In 1968, Hartke and
Rossbuch found that the anhydrous ethereal tetrafluoroboric acid
could promote the dimerization of carbodiimides to give symmetric
1,3-diazetidine-2,4-diimine derivative in good yields.[5] With these
pioneer works, various 1,3-diazetidine-2,4-diimine derivatives were
prepared from the correspondingcarbodiimides during the past
decades.[6] However, these methods suffered from the limited
carbodiimides. To the best of our knowledge, there was no report
about the preparation of unsymmetric 1,3-diazetidine-2,4-diimine
Scheme 1. The reactions of amine with isocyanide.
derivatives from isocyanides with amines.
Ito and coworkers initiated the cross coupling reaction of
isocyanide with amine catalyzed by CuCl to give amidines.[7]
Schwartz’s group,[8] Oruu’s group,[9] and Angelici’s groups[10] have
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DOI: 10.1039J/oCu7OrnB0a2l2N55aGme
I2 (20 mol %)
CHP (2 equiv)
Table 1. Scope of amines 1b-l with isocyanides 2aa,b
O2N
N
(1)
NH2
+
C
N
NO2
C
MTBE
N
1a'
2a
R2
3a'a
, 90%
N
R2
I2 (20mol %)
CHP (2 equiv.)
NO2
N
N
R2 NH2
C
2
N
NO2
2
MTBE
N
N
1b-l
2a
I2 (20 mol %)
CHP (2 equiv)
3ba-la
NO2 (2)
O2N
N
N
2
+ 2 C
N
NO2
NH2
MTBE
N
2a
1a
O2N
3aa, 24 h, 64%
N
N
N
N
N
N
NO2
N
NO2
NO2
N
N
N
N
N
O2N
O2N
O2N
3ba,
3ca,
3da,
24 h, 61%
24 h, 71%
24 h, 89%
Ph
N
N
N
Ph
NO2
N
N
NO2
N
N
N
N
NO2
N
Scheme 2. The reaction of amines with 4-nitryl isocyanide 2a.
N
N
O2N
O2N
O2N
3ea,
3fa,
3ga,
24 h, 86%
24 h, 69%
24 h, 67%
In our previous work, the reaction of 4-nitryl isocyanide 2a with t-
butylamine 1a’ under I2/CHP conditions easily afforded the
corresponding carbodiimide 3a’a in 90% yield. In order to further
explore the scope of amines, we tried the reaction of 4-nitryl
isocyanide 2a with n-butylamine 1a instead of t-butylamine 1a’
under the identical reaction conditions. To our surprise, N-(1-butyl-
4-(butylimino)-3-(4-nitrophenyl)-1,3-diazetidin-2-ylidene)-4-
nitroaniline 3aa was isolated in 64% yield instead of carbodiimide
(Scheme 2, eq. 2). The structure of 3aa was confirmed by NMR, IR,
HRMS and further confirmed by X-Ray crystal structure.[13] This
result indicates that the reaction of suitable amines and isocyanides
could direct result in 1,3-diazetidine-2,4-diimine derivatives
efficiently under the above conditions.
O
N
O
Ph
O
O
N
N
O
N
O
Ph
NO2
NO2
N
N
N
N
NO2
N
N
N
N
O2N
O2N
O2N
3ha, 24 h, 72%
3ia, 24 h, 75%
3ja, 24 h,57%
HN
N
N
N
HN
NO2
N
N
NO2
N
N
N
O2N
O2N
3ka,
24 h, messy
3la, 24 h, N.D.
With this promising result in hand, various primary amines 1b-l
were applied to the reactions with 1-isocyano-4-nitrobenzene 2a.
The results were summarized in Table 1. A range of amines such as
aReaction condition: amine (0.5 mmol), 4-nitryl isocyanide 2a (1.2
equiv, 0.6 mmol), I2 (20 mol %), and CHP (2 equiv) in 3 mL MTBE
(methyl tert-butyl ether) at 55 °C. bIsolated yields.
n-propylamine 1b, n-pentylamine 1c,
n-hexylamine 1d, i-
butylamine 1e, and i-pentylamine 1f reacted smoothly to afford the
corresponding 4-membered 1,3-diazetidine diimine derivatives 3ba-
fa in moderate to good yields with high efficiency. Benzylamine 1g
and 1h can also participate in the reaction with 2a to furnish the
desired products 3ga and 3ha in 86% and 72% yileds, respectively.
It is noteworthy that acetal and ether fucntionalized amines did not
affect the reaction efficiency. The reaction of 2,2-
dimethoxyethanamine 1i and 3-methoxypropan-1-amine 1j with 2a
afforded 3ia and 3ja in 75% and 57% yields, respectively.
Unfortunately, tryptamine 1k and allylaminewith 1l are not reactive
under our optimized conditions, which both failed to give 1,3-
diazetidine-2,4-diimine derivatives or carbodiimides.
Next, we explored the aryl isocyanide scope by the reaction with
n-butylamine 1a under our standard conditions (Table 2). The aryl
isocyanide 2b bearing electron-withdrawing group CN could
smoothyl afford the 1,3-diazetidine-2,4-diimine 3ab in 81% yield.
The aryl isocyanides 2c and 2d bearing COOMe and COOEt
resulted in lower efficiency, affording 3ac and 3ad in 30% and 49%
yields, respectively. Then, the bulky 1-isocyano-2-nitrobenzene 2e
was used, unfortunately, we could not get the product 3ae. But, 1-
isocyano-2-nitrobenzene 2f reacted with n-butyl amine 1a could
obtain the product 3af in the yield of 61%. Unfortunately, 1-
isocyano-4-methoxybenzene 2g was reacted with n-butylamine 1a to
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB02255G
obtain the corresponding product in trace amount. However, the reactions failed to afford the corresponding 1,3-diazetidine-2,4-
reactions of n-butylamine 1a with the 1-chloro-1-isocyano-4- diimine derivative 3aa (Scheme 3, eq. 4).
methylbenzene 2j, 1-isocyano-4-methylbenzene 2i, and bulkyl aryl
isocyanide 2h were messy, respectively. These results indicated that
the substituents on the aromatic ring showed strong effects on the
electron density of aryl isocyanides and their reactivities.
Table 2. Scope of isocyanides 2b-j with
n
-butylamine 1aa,b
I2 (20 mol %)
CHP (2 equiv)
N
2
NH2
1a
2
C
N
Ar
N Ar
N
MTBE
2b-j
N
Ar
3ab-aj
N
N
N
N
N
N
CO2Et
N
N
N
N
CN
N
N
COMe
EtO2
C
NC
MeOC
3ab,
3ac,
3ad,
24 h, 49%
24 h, 81%
24 h, 30%
N
NO2
O2N
N
N
N
N
N
Scheme 3. Scope of amines 1m-q with isocyanides 2a.
N
N
N
N
OCH3
N
To explore the reaction pathway, N-((butylimino)methylene)-4-
nitroaniline 4 was treated under the standard conditions (Scheme 4,
eq. 6). Most of the starting material 4 was recovered and no 1,3-
diazetidine-2,4-diimine product 3aa was detected, which indicated
that 4 was not the reaction intermediate to establish 1,3-diazetidine-
2,4-diimine derivative. Then, we envistigated the reaction of 2-(4-
nitrophenyl)-1,3-dipropylguanidine 5a with 2a under the identical
conditions. To our delight, the reaction underwent well to result in
3aa in 91% yield (Scheme 4, eq. 7). This result meant that the
reaction of 1a and 2a might go through the intermediate guanidine to
construct 1,3-diazetidine-2,4-diimine derivative. We further tried the
reaction of bulkyl guanidine 5b and 5c with 2a under the optimal
conditions, respectively (Scheme 4, eq. 8), of which only trace
amount of 3aa was found. These results solve the problem why 2a
reacted with different amines such as 1a and 1a, to give
O2N
N
NO2
H3CO
3ag,
24 h, trace
3af,
24 h, 61%
3ae,
24 h, trace
N
N
N
N
N
Cl
CH3
N
N
N
N
N
N
N
Cl
H3C
3aj,
24 h, messy
3ai,
24 h, messy
3ah, 24 h, messy
aReaction condition: 1a (0.5 mmol), aromatic isocyanide 2a (1.2
equiv, 0.6 mmol), I2 (20 mol %), and CHP (2 equiv) in 3 mL MTBE
at 55 °C. bIsolated yields.
It is worthy to note that 1-phenylethanamine 1n also reacted well
with 2a under our standard conditions, giving 3na in 54%yield.
However, the reaction of i-propylamine 1m with 2a under the
identical conditions was messy and no desired product 3ma was
observed (Scheme 3, eq. 3). It should be noted that the reaction of p-
toluidine 1o and p-Anisidine 1p with 2a could also undergo
smoothly to give the desired 1,3-diazetidine-2,4-diimines 3oa and
3pa in 84% and 75% yields, respectively (Scheme 3, eq. 4).
However, the reaction of 4-aminobenzonitrile 1q with with 2a failed
to result in the corresponding 1,3-diazetidine-2,4-diimines 3qa. In
addition, we have also tried the reaction of 4-nitroaniline 1r with n-
butyl isocyanide 2i under the identical conditions. Unfortunately, the
carbodiimides
respectively.
and
1,3-diazetidine-2,4-diimine
derivatives,
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DOI: 10.1039/C7OB02255G
2,4-diimine derivatives in up to 89% yields. This work not only
enriched the cross coupling reaction of isocyanide with amine, but
also provided a practical protocol for the direct synthesis of
unsymmetric 1,3-diazetidine-2,4-diimine derivatives under mild
conditions. Further studies to understand the mechanism of this
iodine catalyzed insertion reaction isocyanide with amine are
ongoing in our laboratory.
Acknowledgements
We gratefully acknowledge the National Natural Science Foundation
of China (21772137, 21672157, 21542015), PAPD, the Major Basic
Research Project of the Natural Science Foundation of the Jiangsu
Higher Education Institutions (No.16KJA150002), Soochow
University, and State and Local Joint Engineering Laboratory for
Novel Functional Polymeric Materials for financial support.
Scheme 4. The reaction of 4, 5 under the optimal conditions.
Based on the above results, we proposed a reasonable mechanism
for the reaction as shown in Scheme 5. The 1,1-addition reaction of
isocyanide with iodine affords intermediate A.[11,14] A reacts with
amine to afford intermediate B via dehydrohalogenation. The
intermediate B reacts with less bulkyl primary amine, which leads to
carbodiimide through intramolecular dehydrohalogenation. The
intermediate B with bulkyl primary amine undergo a second time
dehydrohalogenation to give guanidine intermediate C. The tautomer
D of C reacts with A to give intermediate E. Following another
subsequently intramolecular dehydrohalogenation, 1,3-diazetidine-
2,4-diimine is formed. Another possible pathway for the reaction is
that the tautomer F of B reacts with A resulting in the intermediate
G. G subsequently undergoes two times dehydrohalogenation to
give 1,3-diazetidine-2,4-diimine.
Notes and references
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science & Collaborative
Innovation Center of Suzhou Nano Science and Technology, Soochow
b
University, Suzhou, 215123, P. R. China; WISPO Advanced Materials
(SuZhou) Co., Ltd. Room D-904, No. 338 Ruoshui Street, Suzhou
Industrial Park, Suzhou, 215123, People’s Republic of China; Fax:+86-
512-65880307; Tel:+86-512-65880307; E-mail: shunyi@suda.edu.cn,
shunjun@suda.edu.cn
† Electronic Supplementary Information (ESI) available: For ESI or other
electronic format see: 10.1039/c000000x/
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In conclusion, we have developed a novel I2/CHP mediated cross
coupling reaction of isocyanides with readily accessible amines via 4
new C-N bonds formation, affording unsymmetric 1,3-diazetidine-
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02255G
I2/CHP
Mediated
[1+1+1+1]
Cyclization
of
Aromaticisocyanide with Amine to Construct
1,3-Diazetidine-2,4-diimine Derivatives
Hai-Feng Liu, Tong-Hao Zhu, Pei Xu, Shun-Yi Wang,* and Shun-Jun Ji*
R1
I2 (20mol%)
N
CHP (2 equiv.)
2 R1 NH2
2 C
N
EWG
EWG
R1
N
N
MTBE
N
16 examples
yields up to 89%
Metal-free
4 new C-N bonds formation
GWE
EWG = NO2, CN, COMe, CO2Et
An I2/CHP (cumene hydroperoxide) mediated [1+1+1+1] cyclization of aromatic isocyanide with
readily accessible amine via 4 new C-N bonds formation has been developed to construct
unsymmetric 1,3-diazetidine-2,4-diimine derivatives under mild conditions.